Development of Specific Gamma Secretase Inhibitors

Development of Specific Gamma Secretase Inhibitors

Jessica Ahmed (Charité Universitaetsmedizin Berlin, Germany)
Copyright: © 2009 |Pages: 15
DOI: 10.4018/978-1-60566-076-9.ch025
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Secretases are aspartic proteases, which specifically trim important, medically relevant targets such as the amyloid-precursor protein (APP) or the Notch-receptor. Therefore, changes in their activity can lead to dramatic diseases like M. Alzheimer caused by aggregation of peptidic fragments. On the other hand, the secretases are interesting targets for molecular therapy of the multiple myeloma, because the over-expressed Notch-receptor does not emerge into the native conformation until the cleavage by the presenilin, the active and catalytic subunit of the gamma secretase, occurs. Here, we focus on a novel methodology of structure-based drug development, feasible without prior knowledge of the target structure— analogy modeling. This combination of similarity screening, fold recognition, ligand-supported modeling, and docking is exemplarily illustrated for the structure of presenilin and specific inhibitors thereof.
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Aspartic proteases have received considerable attention as potential targets for pharmaceutical intervention since many play important roles in physiological and pathological processes. Despite numerous efforts, the only inhibitors for aspartic proteases currently on the market are directed against the HIV protease, an aspartic protease of viral origin (Eder et al. 2007). All other known aspartic protease inhibitors including those targeting renin, BACE1 and gamma secretase (Tsai et al. 2002) did not yet overcome the clinical or preclinical development due to problems regarding their specificity.

Alzheimer disease (AD) is the most frequent cause of dementia. About five million patients in the seven largest Western economies suffer from that disease. The common form affects humans over 60 years of age and its incidence increases as age advances. AD is characterized by a progressive loss of short-term memory and impaired cognitive function. In later stages additional symptoms aggravate the situation and patients become totally unable to care for themselves. AD is associated with an accumulation of amyloid plaques and neurofibrillary tangles in the brain. These morphological alterations are believed to be causally related to the neurodegenerative process. The beta-amyloid is produced by proteolytic cleavage of amyloid precursor protein (APP) first by beta and then by gamma secretases (Figure 1).

Figure 1.

Processing scheme for the ß-amyloid precursor protein. APP (Amyloid Precursor Protein) is processed in two steps. First, beta secretase generates two fragments, the beta-amyloid precursor peptide and the C-terminal fragment (CTF-ß) C99 fragment. In a second step, the gamma secretase cleaves the C99 fragment into an Aß fragment and AICD (APP Intracellular Domain). Sometimes the gamma secretase generates an Aß fragment with 42 amino acids instead of 40. The 42 peptide aggregates rapidly to amyloid plaques with the fatal consequence that the nerve cell degrades (Figure adopted from Wrede, 2005).


Beta secretase (also known as BACE1, Asp2, Memapsin) is a transmembrane aspartyl protease that generates the N-terminus of beta-amyloid by cleaving APP on the luminal or extracellular side into beta-APP and C99. BACE1 is a prominent target for the treatment and prevention of AD. Since it catalyses a pivotal step in amyloid production, its inhibition should have a positive impact on the progression of the disease (Sinha et al. 1999). In detail, the molecular cause of the severe AD is the aggregation of short peptides with the length of 42 amino acids. These amyloid plaques forming peptides are a fragmentation product of the C99 peptide after hydrolysis by the gamma secretase. The regular function of this protease generates the soluble beta-peptide with 40 amino acids in length.


Role Of Secretases In Cancer

Multiple myeloma (also known as plasma cell myeloma, or as Kahler’s disease) is a type of cancer of plasma cells, which are immune cells in the bone marrow producing antibodies. Multiple myeloma is the second most prevalent blood cancer (10%) after non-Hodgkin’s lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths.

Myeloma is regarded as incurable and, therefore, novel therapeutic approaches like proteasome inhibitors or specific gamma secretase inhibitors are in great demand.

Key Terms in this Chapter

BACE1: BACE1 is a synonym of the beta secretase, which is an enzyme of the aspartic protease family and cleaves the APP. It is involved in Alzheimer development.

TACE: Tumor Necrosis Factor Alpha Converting Enzyme is a metalloprotease which is responsible for the cleavage of Notch outside the membrane

AD: Alzheimer Disease is a neurodegenerative disease, which primarily occurs in groups at the age of 65. About 60 percent of all dementia is caused by AD.

X-Ray: Electromagnetic radiation, which is also used for crystallography of unknown structures.

NMR: Nuclear Magnetic Resonance is a spectrometric method for determination and analysis of structures and dynamics of molecules.

GSK-3: Glycogen Synthase Kinase 3 is a serine/threonine protein kinase.

APP: (Beta-) Amyloid Precursor Protein is an integrale membrane protein, which might be involved in the development of synapses.

TSE: Transmissible Spongiform Encephalopathies, a condition affecting the brain or nervous system of humans and animals. The main hypothesis for TSE is transmission by prions.

HTS: High Throughput Screening is an approach, which involves the screening of large compound libraries, which allows identification of active molecules in experimental (e.g. cell) assays.

RMSD: Root Mean Square Deviation. In this chapter, the rmsd-value reflects the grade of similarity of two structures.

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